Polymerizable dye

ABSTRACT

Dye monomers of the general chemical formula ##STR1## where X denotes an unsaturated polymerizable organic radical; and 
     R is an organic diradical with 2 to 12 carbon atoms.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. Application Ser. No.348,543 filed May 2, 1989.

SUMMARY OF THE INVENTION

This invention relates to a class of novel compounds which are useful ascomonomers to tint contact lens materials. These compounds arerepresented by the general formula ##STR2## where X denotes apolymerizable, unsaturated organic radical; and R denotes an organicdiradical with 2 to 12 carbon atoms. The invention also relates tocopolymers of the above compounds which are useful as materials inbiomechanical applications.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel class of compounds which areparticularly useful as comonomers to impart a blue color inbiomechanical devices. Specifically, the present invention relates tocompounds represented by the foregoing general formula wherein R and Xare defined as follows: R is a divalent organic radical with 2 to 12carbon atoms and X is a polymerizable, unsaturated radical, such as amethacrylate, acrylate, vinyl carbonyl, or vinyl carbamate functionalmoieties. Compounds wherein R is a divalent phenyl alkyl radical havebeen found to be especially useful polymerizable dyes.

The general synthetic scheme for producing the comonomers of the presentinvention is illustrated below. ##STR3##

The comonomers produced by the General Synthetic Scheme outlined abovehave several characteristics which distinguish them over dye comonomersused in biomechanical devices previously. For instance, the presentinvention dye monomers are compatible with many monomers used to producebiomechanical materials. This allows the dye to be mixed with the bulkmonomer prior to the polymerization of that comonomer.

Furthermore, the functionality of the present dye comonomers allows themto be more completely polymerized with the bulk monomers used to producestate of the art biomechanical materials. This ensures that the presentinvention dye comonomers become integral parts of the copolymer's matrixand cannot be leached out of that matrix by conditions (e.g.,physiological conditions) that are encountered by hydrogel materials,especially biomechanical materials such as contact lenses.

Furthermore, due to the solution compatibility of these dye comonomerswith other comonomers, they can be used in various concentration rangeswhich allows them to be used as tinting (or coloring) agents. Thisresult is a particularly important characteristic in contact lensmaterials and has heretofore been unavailable in the art.

The comonomer dyes of the present invention can be used to producebiomechanical materials in conjunction with known monomers whilemaintaining all of the advantageous characteristics of polymers producedfrom the known monomers. This allows for the production of copolymerswhich are tinted or colored and which still maintain the beneficialphysiological characteristics required for biomechanical materials.

The monomers which the present invention can be copolymerized withinclude both hydrophilic and hydrophobic monomers. Biomechanicalmaterials, of course, include copolymeric mixtures. The compounds of thepresent invention are used as an additional agent in the prepolymermixtures disclosed in the art. The dye compound of this invention isadded in amounts sufficient to impart the desired color intensity. Theupper limit of comonomer dye concentration may be restricted by theamount of crosslinking effected by the difunctional dye molecule.Typically the dye concentration will not exceed 5% of the total monomermixture. More typically the dye concentration will range from about0.001 to about 2 weight percent of the total monomer mixture. Theconcentration will of course determine the color intensity of theresulting copolymer.

The polymerizable dye of this invention is particularly useful to colorhydrogel materials. Hydrogel materials (i.e., water-containing polymers)are prepared from a wide variety of copolymeric mixtures characterizedby the presence of hydrophilic monomers. Examples of hydrophilicmonomers are 2-hydroxyethylmethacrylate, N-vinyl pyrrolidone, andmethacrylic acid. Copolymeric mixtures used to prepare hydrogels mayalso include polymers such as polyvinyl alcohol and polyethylene glycol.Hydrogels for contact lenses are generally made by the polymerization ofhydrophilic monomers (e.g., 2-hydroxyethylmethacrylate or N-vinylpyrrolidone) with a crosslinking agent. Useful hydrogels are alsoobtained by the copolymerization and crosslinking of hydrophilic andhydrophobic monomers to obtain the desired level of water absorption inthe gel. Suitable hydrogels are further exemplified by the materialsdescribed in U.S. Pat. No. Re. 27,401; U.S. Pat. No. 3,532,679; and U.S.Pat. No. 3,937,680.

The monomers of the present invention can also be used in conjunctionwith rigid gas permeable contact lens formulations known in the art asexemplified in U.S. Pat. Nos. Re. 31,406, U.S. Pat. No. 4,424,328, U.S.Pat. No. 4,139,548, U.S. Pat. No. 4,433,111, U.S. Pat. No. 4,152,508,U.S. Pat. No. 4,450,264, U.S. Pat. No. 4,153,641, U.S. Pat. No.4,540,761, U.S. Pat. No. 4,372,203, and U.S. Pat. No. 3,950,315.

The invention compounds may also be used as comonomers with siliconebased systems. Silicones are also well known in the art and areexemplified by the following U.S. Pat. Nos.: U.S. Pat. No. 4,136,250,U.S. Pat. No. 3,518,324, and U.S. Pat. No. 4,138,382.

The following examples are not intended to exemplify the full scope ofthe present invention. They are meant to illustrate certain specificexamples of the present invention to those skilled in the art and toprovide sufficient basis for those skilled in the art to practice theirinvention.

EXAMPLES EXAMPLE 1a Synthesis of1,4-Bis(2-methacrylamidoethylamino)anthraquinone(I)

Into a 250 ml 2 neck round bottom flask equipped with a thermometer wasplaced 6.0 g of leucoquinizarin and a stir bar, and the flask wasflushed with nitrogen. To this was added 75 ml of ethylene diaminethrough which nitrogene had been bubbled of 15 minutes. While keepingthe reactants under nitrogen, the solution was heated to 50° C. for onehour during which the solution turned green. The nitrogen blanket wasthen removed and air was bubbled through the solution for one hour,keeping the temperature at 50° C., causing the solution to turn blue.Water, 250 ml, was added and the intermediate product was isolated byfiltration, washed with water and air dried. The intermediate wasrecrystallized from acetonitrile. The final isolated yield was 37%. Asolution of 1.0 g of the intermediate in 250 ml of methanol was cooledto <3° C. using an ice bath. To this was added 5.0 ml of triethylamineand 3.5 ml of methacryloyl chloride. After one hour the reaction wascomplete. The product was precipitated by the addition of 500 ml ofwater, isolated by filtration, washed with 1:1 methanol:water and thenwater, and air dried giving an isolated yield of 80%.

According to the above procedure, the following compounds were prepared:

1,4-bis(2-acrylamidoethylamino)anthraquinone.

1,4-bis(3-methacrylamidopropylamino)anthraquinone (II),

1,4-bis(3-methacrylamido-2,2-dimethylproylamino) anthraquinone (III),

1,4-bis(2-acrylamidocyclohexylamino)anthraquinone, and1.4-bis(2-methacrylamidocyclohexylamino)anthraquinone (IV).

EXAMPLE 1b Synthesis of1,4-Bis(3-methacryloxypropylamino)anthraquinone(V)

The intermediate was prepared as before using 8.0 g of leucoquinizarinand 50 ml of 3-aminopropanol giving a recrystallized yield of 23%. To asolution of 1.0 g of the intermediate in 200 ml of acetonitrile wasadded 3.0 ml of triethylamine and 1.5 ml of methacryloyl chloride atroom temperature. The reaction was complete after 1/2 hour. The solutionwas diluted to 1 liter with water and 1.0 g of NaOH was added. The gummysolids were isolated on fluted filter paper, redissolved in 200 ml ofacetone and reprecipitated by the addition of 200 ml of water. Theproduct was isolated by filtration on a fritted filter, washed with 1:1acetone:water, water and air dried. The isolated yield was 20%.

EXAMPLE 1c Synthesis of1,4-Bis(1-methacryloxy-2-butylamino)anthraquinone(VI)

A mixture of 15 g of quinizarin, 75 ml of (±)-2-amino-1-butanol and 100ml of water was heated under nitrogen at 90° C. for 7.5 hours and thendiluted to 500 ml to precipitate the product. The intermediate wasisolated by filtration, washed with water and air dried.Recrystallization from toluene gave a yield of 52%. To a solution of 2 gof the intermediate in 100 ml of dry acetonitrile was added 4.0 ml oftriethylamine and 3.0 ml of methacryloyl chloride. After 1/2 hour, 300ml of ethylene glycol was added and 10 minutes later the solution wasdiluted to 1 liter with water. The tacky product was filtered out of thesolution, redissolved in 200 ml of acetone and precipitated by theaddition of 500 ml of water. The wet product was redissolved in 200 mlof acetone a second time and precipitated by the addition of 300 ml ofwater, isolated by filtration, washed with water and air dried. Theisolated yield was 52%. The TLC showed the expected two spots for boththe intermediate and the final product.

EXAMPLE 1d Synthesis of1,4-Bis(1-methacryloxy-2-pentylamino)anthraquinone(VII)

A deoxygenated solution of 3.0 g of leucoquinizarin, 10.0 g of(±)-2-amino-1-pentanol and 50 ml of triethylamine was heated at 60° C.under nitrogen overnight. Air was then bubbled through the solution at55° C. for 3 hours. The resulting oil was diluted with 250 ml ofmethanol and then with 250 ml of water to precipitate the intermediate,which was isolated by filtration, washed with 2:1 water:methanol and thewater, and air dried. The isolated yield was 75%. To a solution of 2.0 gof the intermediate in 50 ml of dry acetonitrile was added 4.0 ml oftriethylamine and 2.0 ml of methacryloyl chloride. After 30 minutes atroom temperature, the reaction was completed. The solution was dilutedwith 50 ml of ethylene glycol followed by 400 ml of water 15 minuteslater. After vigorous stirring for one hour, most of the gummy productwas sticking to the sides of the flask. The solution was filtered andthe solids were dissolved in 500 ml of methanol. The product wasreprecipitated by the addition of 500 ml of water, isolated byfiltration, washed with 1:1 water:methanol followed by water and airdried. Isolated yield was 34%.

EXAMPLE 1e Synthesis of1,4-Bis(4-methacryloxycyclohexylamino)anthraquinone(VIII)

A deoxygenated solution of 10.0 g of trans-4-aminocyclohexanolhydrochloride, 2.76 g of NaOH, 25 ml of water and 45 ml of triethylaminewas added to a nitrogen filled flask containing 2.0 g of leucoquinizarinand the mixture was heated at 55° C. for two hours. Air was then bubbledthrough the solution overnight at 55° C. to form the crude intermediate.The slurry was diluted to 250 ml with water and the solids were isolatedby filtration. Unoxidized product was removed by placing the solids in500 ml of boiling 2-propanol for one hour, cooling and filtering. Thepurified intermediate was washed with methanol and air dried. Theisolated yield was 61%. To a slurry of 1.5 g of the intermediate in 100ml of toluene was added 5.0 ml of pyridine and 1.4 ml of methacyloylchloride. After boiling for 10 minutes, the product was formed and thesolvent was removed on a rotovap. The solids were dissolved in 500 ml ofacetone and the product was precipitated by the addition of 500 ml ofwater. The fine precipitate was isolated on fluted filter paper,redissolved in acetone, precipitated with water and the product wasisolated by filtration. After washing with water, the product was airdried. The yield was 60%.

EXAMPLE 1f Synthesis of1,4-Bis(2-methacryloxycyclohexylamino)anthraquinone(IX)

A deoxygenated solution of 10.9 g of 2-aminocyclohexanol hydrochloride,2.58 g of NaOH, 50 ml of water and 100 ml of triethylamine was added toa nitrogen filled flask containing 2.0 g of leucoquinizarin and themixture was heated at 55° C. for four hours. Air was then bubbledthrough the solution overnight with the temperature reaching 80° C.After diluting with water, the solids were filtered out. The solids wereslurried and washed with acetone until the filtrate was light blue. Theyield of the air dried product was 42%. Over a 1/2 hour period of time,a total of 2.6 ml of methacryloyl chloride, 4.0 ml of triethylamine and2.0 ml of pyridine was added to a slurry of 1.0 g of the intermediate in100 ml of dry acetonitrile. Product was formed by boiling the mixturefor one hour. Water, 25 ml, was added and the solvents were rotovapedoff. The solids were slurried in 1 liter of water containing 0.5 g ofNaOH for 1/2 hour and the product was isolated from the highly coloredsolution by filtration. The product was dissolved in 300 ml of acetone,precipitated by the addition of 600 ml of water and isolated byfiltration several times until the filtrated was light blue. The yieldof the air dried product was 20%.

EXAMPLE 1g Synthesis of1,4-Bis(2-methacryloxy-1-phenylethylamino)-anthraquinone(X)

In an oxygen free solution, 3.0 g of leucoquinizarin and 10.0 g ofL-2-phenylglycinol in 150 ml of triethylamine were reacted overnight at55° C. Air was then bubbled through the solution for 3 hours at 55° C.and the mixture was reduced to dryness on a rotovap. The solids weredissolved in acetone and the intermediate was precipitated by theaddition water containing NaOH. The product was isolated from the highlycolored solution by filtration, washed and air dried. The yield of theintermediate was 45%. Two grams of the intermediate was dissolved in 100ml of dry acetonitrile to which was added 4.0 ml of triethylamine and2.5 ml of methacyoyl chloride. After 1/2 hour the reaction was complete.Methanol, 25 ml, was added and the solvents were rotovaped off. Theproduct was dissolved in 250 ml of water and isolated by filtrationseveral times until the filtrate was light blue. The yield of the airdried product was 33%.

EXAMPLE 1h Synthesis of 1,4-Bis(1-methacryloxy-3-methyl-2-pentylamino)anthraquinone(XI)

A 1.5 g sample of leucoquinizarin was reacted with 5.0 g ofL-isoleucinol in 50 ml of triethylamine under nitrogen for 6 hours at55° C. Air was then bubbled through the solution for 8 hours with thetemperature reaching 80° C. at one point. The mixture was diluted with1:1 methanol:water and filtered to isolate the intermediate. Theintermediate was washed with the same solvent mixture until the filtratewas light blue. The yield of the air dried intermediate was 87%. TLCshowed that the intermediate still contained unoxidized andmono-substituted impurities. To a solution of 1.23 g of the impureintermediate in 50 ml of dry acetonitrile was added 3.0 ml oftriethylamine and 1.5 ml of methacyloyl chloride. The reaction wascomplete after 15 minutes at room temperature. Methanol, 50 ml, wasadded and the solution was evaporated to dryness. The crude product waspurified by column chromatography over silica gel using 1:1toluene:chloroform as the eluent. When the solvent was evaporated, itwas found that the product was tacky. Repeated dissolving in methanoland stripping resulted in a dry product. The yield was 63%.

EXAMPLE 1i Synthesis of 1,4-Bis(4-(2-methacryloxyethyl)phenyamino-anthraquinone (XII)

A 3.0 g sample of leuquinizarin was heated with 10.0 g of4-aminophenethyl alcohol (mp 113° C.) under nitrogen at reflux (˜150°C.) for 5 hours. TLC showed no further changes occurring. Ethyleneglycol, 25 ml, was added and air was bubbled through the hot solutionfor 3 hours. After cooling, the resulting solid cake was broken up andthe solids were dissolved in 1 liter of acetone, the solution filteredand the intermediate was precipitated by the addition of 1 liter of NaOHin water. The intermediate was isolated by filtration, washed with waterand air dried. The yield was 38%. To a slurry of 1.6 g of theintermediate in 30 ml of dry acetonitrile was added 3.2 ml oftriethylamine and 1.6 ml of methacrylol chloride at room temperature.After 30 minutes the reaction was complete and 15 ml of ethylene glycolwas added. After 15 minutes, the product was precipitated by dilutingthe solution to 1 liter with water and isolated by filtration. Theproduct was purified by dissolving 800 ml of acetone and precipitated bythe addition of 400 ml of water. The product was isolated from the deeprust colored solution by filtration, washed with 1:1 acetone:water andair dried. The isolated yield was 57%.

EXAMPLE 2 Preparation of Tinted Copolymeric Contact Lens Materials

A monomer mix was prepared from the following formulation:

2-hydroxymethacrylate (HEMA): 99.49 wt %

Ethylene Glycol Dimethacrylate (EGDMA): 0.34 wt %

Benzo Methyl Ether Catalyst (NVP): 0.17 wt %

monomer I: 200 ppm

Monomer (I) is the dye molecule synthesized in Example 1(a). The monomermixture was polymerized between silicone treated glass plates using afluorescent UV source. Similar pHEMA films were cast using 200 ppm ofthe various monomers synthesized in Example 1.

EXAMPLE 3

Discs were cut from the film prepared from monomer I (as described inExample 2). These untinted discs were tinted by a state of the artmethod using Procian blue (Procian Blue discs). The visible spectra ofthe film discs of example 2 and the Procian Blue discs were compared.The discs were then subjected to accelerated hydrolysis testing and theresultant visible spectra were again compared. Both types of discsshowed about the same loss of color intensity. However, the loss of thecolor intensity in the Procian disc was from loss of dye from the discwhereas loss of color intensity in the monomer I disc was due to thehydrolysis of the amine functionality rather than actual monomer loss.

EXAMPLE 4

pHEMA films were made with 200 ppm of each of the monomers I, II, III,and IV. Incorporation of the bismethacrylamide monomers into the pHEMAwas tested with the following results:

    ______________________________________                                        Monomer   Bridge (R)      % Incorporation                                     ______________________________________                                        I             --(CH.sub.2).sub.2 --                                                                         92                                              II            --(CH.sub.2).sub.3 --                                                                         90                                              III           --CH.sub.2 C(CH.sub.3).sub.2 --CH.sub.2 --                                                    82                                              IV            1,2-cyclohexylene                                                                             82                                              ______________________________________                                    

The hydrolytic stability of the final polymeric material was tested byboiling the samples in buffered saline solution. After 4 weeks the lossof color intensity was as follows:

    ______________________________________                                                      % Loss                                                          Monomer         at 600 nm                                                                              at 640 nm                                            ______________________________________                                        I                   18       26                                               II                  16       28                                               III                 14       26                                               IV                   5        7                                               ______________________________________                                    

The monomer with the largest R radical produced the most stablecopolymeric material.

EXAMPLE 5

The dimethyacrylate ester monomers were tested for incorporation in to apHEMA material and for stability. Incorporation was as follows:

    ______________________________________                                        Monomer   Bridge (R) Precursor                                                                           % Incorporation                                    ______________________________________                                        V             3-aminopropanol  100                                            VI            2-aminobutanol   98                                             VII           2-aminopentanol  98                                             VIII          4-aminocyclohexanol                                                                            98                                             IX            2-aminocyclohexanol                                                                            95                                             X             2-amino-2-phenylethanol                                                                        97                                             XI            2-amino-3-methylpentanol                                                                       97                                             XII           2-(4-aminophenyl)ethanol                                                                       99                                             ______________________________________                                    

The hydrolytic stability of the pHEMA films were tested as described inExample 4. After 4 weeks, the loss of color intensity was as follows:

    ______________________________________                                                       % of Loss                                                      Monomer         at 600 nm                                                                              at 640 nm                                            ______________________________________                                        V                   49       53                                               VI                  14       27                                               VII                 16       28                                               VIII                25       38                                               IX      (3 weeks)   11       25                                               X                   15       24                                               XI                  14       29                                               XII                  6        6                                               ______________________________________                                    

EXAMPLE 6

Films were cast from a monomer mix as described in Example 2 except thatthe mix contained 150 ppm of monomer XII. The control was untinted filmcast from the same lot of monomer mix. Film properties were measuredwith the following results:

    ______________________________________                                                       Monomer XII Control                                            Test           Film        Film                                               ______________________________________                                        modulus (g/mm.sup.2)                                                                          57          59                                                tensile        66          71                                                 % elongation   280         290                                                initial teat   6.8         6.7                                                propagation tear                                                                             4.9         5.0                                                % H.sub.2 O    37.3        37.9                                               O.sub.2 permeability                                                                         8.9 × 10.sup.-11                                                                    9.2 × 10.sup.-11                             (cm.sup.3 × cm/sec × cm.sup.2 × @ 35 C.)                    ______________________________________                                    

The results show that the monomer does not affect the physicalcharacteristics of standard contact lens materials.

EXAMPLE 7

A monomer mix was prepared from the following formulation:

Methyl methacrylate: 36.4 grams

NVP: 88.2 grams

EGDMA: 0.033 grams

Allyl methacrylate: 0.24 grams

VAZO-64 Catalyst: 0.12 grams

Monomer XII: 450 ppm

The monomer mix was heat cured into rods from which buttoms were cut anddiscs were lathed. The buttons and discs were blue-green.

What is claimed is:
 1. Compounds having the general chemical formula ##STR4## wherein: R denotes a divalent radical with 1 to 12 carbon atoms; andX denotes a polymerizable unsaturated organic radical.
 2. The compound of claim 1 wherein X is described by the formula --Y--CO--C(Z)═CH₂ wherein Y is --O-- or --NH-- and Z is hydrogen or methyl.
 3. The compound of claim 2 wherein R is a divalent phenylalkyl radical.
 4. The compound 1,4-bis(4-(2-methacryloxyethyl) phenylamino)anthraquinone. 